tbuckley/cabot-search huggingface dataset:
Abstract 966: All stressed out: Phenoytpe plasticity and therapy resistance in melanoma
Authors: Jasmin Giles, Maria Biancaniello, Mitchell Fane, Gretchen Alicea, Andrew Kossenkov, Amanpreet Kaur, Vito Rebecca, Xiaowei Xu, Meenhard Herlyn, Maureen Murphy, Ashani Weeraratna, Marie R. Webster
Journal: Cancer Research (2022)

Abstract Metastatic melanoma is an aggressive disease. Despite recent improvements in therapy, drug resistant populations emerge even in drug-sensitive tumors. The ability to adapt to multiple types of stress contributes to tumor progression and therapy resistance. We have found a subset of melanoma cells with high Wnt5A and wild type p53 expression can transition to a slow-cycling state, rendering them resistant to most targeted therapy. Multiple types of stress, including DNA damage, targeted therapy, and aging increase Wnt5A and p53 in these metastatic cells. Inhibiting p53 blocks the slow cycling phenotype and promotes sensitivity to targeted therapy. A single dose of a p53 inhibitor at the commencement of BRAF/MEKi therapy was sufficient to prolong sensitivity to BRAF/MEKi therapy in Yumm1.7 derived tumors grown in aged mice (&amp;gt; 52 weeks). Upon analysis of PDX tumors with WTp53, treated with BRAF/MEKi combination or BRAFi therapy, we observed an increase in p53 positive cells as well as an increase in Wnt5A expression, further linking Wnt5A and p53 with resistance to targeted therapy. These data suggest that melanoma cells require p53 to survive multiple types of stress and that taking the paradoxical approach of inhibiting rather than activating WTp53 may sensitize previously resistant metastatic melanoma cells to therapy by temporarily driving them into a rapidly cycling state. WTp53 is typically thought of as a tumor suppressor due to its ability to regulate cell proliferation, stress response, and cell death. However, in metastatic melanoma cells, p53 promotes the expression of EDIL3, FAP, MMP3, and netrin G1, which are associated with poor prognosis, increased angiogenesis, and metastasis in multiple types of cancer. These data suggest that p53, typically thought of as a tumor suppressor, may be promoting the survival of a subset of highly resistant metastatic cells. Citation Format: Jasmin Giles, Maria Biancaniello, Mitchell Fane, Gretchen Alicea, Andrew Kossenkov, Amanpreet Kaur, Vito Rebecca, Xiaowei Xu, Meenhard Herlyn, Maureen Murphy, Ashani Weeraratna, Marie R. Webster. All stressed out: Phenoytpe plasticity and therapy resistance in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 966.
Abstract 4121: Durable stable disease with nivolumab, PD-1 inhibitor, and subsequent bevacizumab, Anti-VEGF monoclonal antibody, in long standing recurrent respiratory papillomatosis with lung squamous cell carcinoma
Authors: Horyun Choi, Jinah Kim, Yeun Ho Lee, Leeseul Kim, Young Kwang Chae
Journal: Cancer Research (2022)

Abstract Background: Recurrent respiratory papillomatosis (RRP) is a human papilloma virus (HPV) associated benign disease, which, in rare cases, can develop into lung squamous cell carcinoma. Treatment options are limited with no approved systemic adjuvant therapy and the disease requires frequent surgical resection to prevent airway obstruction. Therefore, expanding available treatment options remains a highly important, but unmet need in RRP. Herein, we present a case of RRP with squamous cell carcinoma of lung that demonstrated durable stable disease with nivolumab and subsequent bevacizumab. Case presentation: A 48-year-old woman with long standing RRP since teenager, who underwent multiple microsuspension laryngoscopies, debridements including laryngeal lesions, and ultimately, 5 years ago, video assisted thoracic surgery (VATS) resection of right upper lobe mass, confirming squamous cell carcinoma, has been managed with debulking surgery on tracheal lesions by ENT on regular basis. Nivolumab, a programmed death-1 blockade, 3 mg/kg every 2 weeks was started given squamous cell carcinoma of lung. Stable disease (SD) in lung lesions was achieved on nivolumab for one year but she required more frequent debulking of tracheal lesions. After multidisciplinary discussion with Otorhinolaryngology, she was started on bevacizumab, vascular endothelial growth factor inhibitor, 10 mg/kg every 6 weeks. Follow-up CT scans in 10 weeks showed a decrease in size of a left lower lobe mass to 27 mm from 32 mm in the previous image. After one year, administration of bevacizumab was spaced out to every 12 weeks. She requires less debulking surgery and the last debulking surgery was approximately 3 years ago. She maintains SD for over 4 years since starting bevacizumab. Discussion: Our patient with RRP and squamous cell carcinoma of lung demonstrated SD on nivolumab before she was switched to bevacizumab. In addition, her SD on bevacizumab of more than 4 years with 12 weeks of maintenance interval is encouraging as there is no current standard of care treatment for RRP. Despite difficulty in running clinical trials in RRP due to its rareness, additional studies evaluating the efficacy of PD-1 inhibitor or anti-VEGF monoclonal antibody on RRP are warranted. Citation Format: Horyun Choi, Jinah Kim, Yeun Ho Lee, Leeseul Kim, Young Kwang Chae. Durable stable disease with nivolumab, PD-1 inhibitor, and subsequent bevacizumab, Anti-VEGF monoclonal antibody, in long standing recurrent respiratory papillomatosis with lung squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4121.
Abstract 2345: Specificity of catechol-O-methyltransferase (COMT) for hydroxyestrogens favors 2-OHEs over 4-OHEs
Authors: Daniel D. Krzizike, Margie L. Clapper, Andrew J. Andrews
Journal: Cancer Research (2022)

Abstract The contribution of estrogen receptor-mediated signaling to cancer progression and metastasis has been well documented. However, much less attention has been given to the role of estrogen metabolism in carcinogenesis. Parent estrogens are metabolized to 2- and 4-hydroxyestrogens (2-OHEs and 4-OHEs) that can retain their estrogenic activity, form reactive quinones that cause DNA damage, or become inactivated primarily by the rate-limiting conjugation enzyme catechol-O-methyltransferase (COMT). The ability of 4-OHEs to induce genomic instability and the malignant transformation of human breast epithelial cells has been reported. Glucuronidation or sulfation of methylated hydroxyestrogens, produced by COMT, increases their solubility and facilitates their excretion via urine or feces. The extent to which catechol estrogens are methylated dictates, in part, their ability to initiate carcinogenesis verses protect against tumor formation. COMT is a ubiquitous polymorphic enzyme that is expressed in humans in both peripheral tissues (soluble, s-COMT) and the central nervous system (membrane-bound). The goal of the present study was to compare the rate at which human wild type (WT) s-COMT and its major polymorphic variant (V108M s-COMT) transfer the methyl group from S-adenosylmethionine to 2-OHE and 4-OHE. This was accomplished by expressing COMT in E. coli, followed by protein purification and steady state Michaelis-Menten kinetics. Production of methylated hydroxyestrogens (2-MeOEs and 4-MeOEs) was quantified using LC-MS/MS methodology. The resulting data indicate that WT s-COMT methylates catechol estrogens more efficiently than V108M s-COMT. In addition, the specificity constant (kcat/KM) of WT s-COMT for methylation of 4-OHE2 was 12-fold greater than that of V108M s-COMT. The kcat/KM of V108M s-COMT was 4-fold greater for 2-OHE2 vs. 4-OHE2. Based on the enhanced catalytic efficiency of WT s-COMT in converting 2-OHEs to 2-MeOEs, 4-OHEs may have greater potential to cause DNA damage. Additional studies are needed to determine if the V108M s-COMT variant contributes to increased risk for cancer. These data provide novel insight into the potential mechanism by which 4-OHEs promote hormone-induced carcinogenesis. This work was supported by an In Vino Vita Award from Fox Chase Cancer Center. Citation Format: Daniel D. Krzizike, Margie L. Clapper, Andrew J. Andrews. Specificity of catechol-O-methyltransferase (COMT) for hydroxyestrogens favors 2-OHEs over 4-OHEs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2345.
Abstract 143: Novel HSP40 or J domain protein inhibitors that deplete misfolded mutant p53
Authors: Tomoo Iwakuma, Shigeto Nishikawa, Atsushi Kaida, Atul Ranjan, Alejandro Parrales, Mohamed A. Alalem, David K. Johnson
Journal: Cancer Research (2022)

Abstract Background: Accumulation of oncogenic mutant p53 (mutp53) greatly contributes to cancer progression. Heat shock protein 40 (HSP40), also known as J-domain proteins (JDPs), has been implicated in stabilization of misfolded mutp53. Specifically, knockdown of DNAJA1, a member of HSP40/JDPs, results in degradation of mainly misfolded mutp53, leading to inhibition of tumor progression. Since no DNAJA1 inhibitors are currently available in clinics, these findings prompted us to identify potential DNAJA1 inhibitors which can induce mutp53 degradation. Methods/Design: An in-silico docking study was performed for binding of the DNAJA1 J-domain to compounds in zinc data base, which identified compound Number7-3. Further analysis suggests three critical amino acids in DNAJA1 for the binding, including Y7, K44, and Q47. Results: Eighteen commercially available analogs of Number7-3 were further examined. Of these, a compound, namely A11, had the strongest activity to deplete both DNAJA1 and misfolded mutp53. A11 reduced protein levels of misfolded mutp53 in concentration- and time-dependent manners without affecting mRNA levels of DNAJA1 and mutp53. Importantly, A11 showed minimal effects on the levels of wild-type p53 and DNA contact mutp53. Treatment of cells expressing misfolded mutp53 with A11 resulted in reduced filopodia formation and cell migration, which was not observed in cells lacking DNAJA1. Moreover, protein levels of a triple mutant DNAJA1 (Y7A/K44A/Q47A) were not altered by A11. Intriguingly, A11 reduced protein levels of several other HSP40/JDPs. Conclusions: Our study, for the first time, has identified a small compound that depletes DNAJA1, leading to reduced levels of misfolded mutp53 and inhibited malignant properties of cancer cells. Citation Format: Tomoo Iwakuma, Shigeto Nishikawa, Atsushi Kaida, Atul Ranjan, Alejandro Parrales, Mohamed A. Alalem, David K. Johnson. Novel HSP40 or J domain protein inhibitors that deplete misfolded mutant p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 143.
Abstract 312: Redirecting T cells to tumor targets with functionally diverse CD3-binding antibodies
Authors: Lindsay DeVorkin, Tim M. Jacobs, Raffi Tonikian, Karine Hervé, Kate Caldwell, Yuri Hwang, Cristina Faralla, Wei Wei, Katherine J. Lam, Harveer Dhupar, Tran NT Tran, Melissa Cid, Lena M. Bolten, Tova Pinsky, Kush Dalal, Kevin A. Heyries, Bryan C. Barnhart
Journal: Cancer Research (2022)

Abstract Bispecific antibodies that redirect cancer-killing T cells towards tumors are promising next-generation cancer therapies. While there are hundreds of T cell engagers (TCEs) in development, there is only one approved and marketed CD3-binding TCE. The high rate of attrition is largely attributable to dose-limiting toxicities, including cytokine release syndrome, due in part to the small pool of high affinity CD3-binding antibodies that are commonly used. The discovery of safe and effective TCEs is limited because diverse panels of parental CD3 antibodies are hard to produce, the pairing of parentals is hard to perfect, and the sheer complexity and volume of data is hard to action. In this study, we will present a panel of functionally diverse, fully human CD3-binding parental antibodies. We will present data characterizing the diversity of our panel across multiple parameters, including sequence diversity, CD3 affinity, epitope binding, T cell activation, cytokine release, and tumor cell killing. Using OrthoMab࣪, our clinically-validated bispecific engineering platform, allows this panel to be tested with a series of tumor-associated antigens (TAAs) in a matrix format. Results from high-throughput production and characterization of bispecific antibodies will be presented. These multidimensional datasets of TCE composition and function allow for the identification of pairs that are optimal candidates for clinical development. This work will show how the diversity of our CD3-binding panel, combined with a robust bispecific protein engineering technology, can be used to quickly assess large and diverse TAA-binding panels discovered through our technology stack. An integrated workflow that doubles the data with diverse panels of parentals, assembles stable, safe, and manufacturable TCEs, and visualizes multidimensional datasets are critical to successfully identifying lead therapeutic candidates to bring the next generation of cancer therapies to patients sooner. Citation Format: Lindsay DeVorkin, Tim M. Jacobs, Raffi Tonikian, Karine Hervé, Kate Caldwell, Yuri Hwang, Cristina Faralla, Wei Wei, Katherine J. Lam, Harveer Dhupar, Tran NT Tran, Melissa Cid, Lena M. Bolten, Tova Pinsky, Kush Dalal, Kevin A. Heyries, Bryan C. Barnhart. Redirecting T cells to tumor targets with functionally diverse CD3-binding antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 312.
Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities
Authors: Sarah J Tabrizi, Carlos Estevez-Fraga, Willeke M C van Roon-Mom, Michael D Flower, Rachael I Scahill, Edward J Wild, Ignacio Muñoz-Sanjuan, Cristina Sampaio, Anne E Rosser, Blair R Leavitt
Journal: The Lancet Neurology (2022)
Abstract 3762: Applications of innovative whole-genome bisulfite sequencing (WGBS) for cancer biomarker discovery in plasma liquid biopsy
Authors: Caila Ruiz, Hanjun Kim, Zhenguo Zhang, Jeffrey Bhasin, Mingda Jin, Yi Xu, Xiaojing Yang
Journal: Cancer Research (2022)

Abstract Circulating cell-free DNA (cfDNA) has been reported to contain valuable genetic and epigenetic information for the diagnosis and prognosis of cancer. Studies have shown that the blood from cancer patients contained more tumor-derived cfDNA compared to the healthy controls. DNA methylation, the most well-studied epigenetic marker, has been validated as one of the key drivers in the development of many diseases including cancer. cfDNA methylation thus holds great potential to become a biomarker that will enable early detection of cancer. However, cfDNA is also a challenging input for library preparation as cfDNA is mostly highly fragmented, and the amount of cfDNA from blood plasma is comparatively low. Therefore, multiple library preparation protocols were evaluated for profiling DNA methylation patterns at single nucleotide resolution from ultra-low amount of blood plasma cfDNA. These methods included two bisulfite conversion-based protocols and an enzymatic based protocol. The bisulfite conversion reaction was optimized allowing a milder treatment for less nucleic acid damage. One of the bisulfite conversion based protocols also contained a further optimized adapter ligation step, allowing a simpler procedure. Circulating cfDNA were extracted from blood plasma of a healthy control, a non-small cell lung cancer patient, and an adenocarcinoma lung cancer patient. 5-ng cfDNA was used as input and the libraries were successfully prepared using all three methods. Each library was sequenced to 300 - 600 million read pairs at a read length of 150 bp, enabling a mean coverage of about 10X per detected CpG, and over 90% of the CpG sites in human genome were detected. Unique alignment rate among all libraries were about or above 80%. The comprehensive coverage of the CpG sites across the entire human genome illustrated that the optimized bisulfite conversion reaction was compatible with fragmented cfDNA, proving the satisfactory efficacy in this simple and classic method for DNA methylation profiling of such a challenging sample type. This opens the door to apply the streamlined and simple Whole-Genome Bisulfite Sequencing (WGBS) protocol for cfDNA methylation profiling, which in turn shall facilitate further understanding in cfDNA epigenetic variations and advance the development of a cancer biomarker from the non-invasive, liquid biopsies. Citation Format: Caila Ruiz, Hanjun Kim, Zhenguo Zhang, Jeffrey Bhasin, Mingda Jin, Yi Xu, Xiaojing Yang. Applications of innovative whole-genome bisulfite sequencing (WGBS) for cancer biomarker discovery in plasma liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3762.
Abstract 5692: Tissue specificity of chromosome aneuploidy correlates with BRCA-associated cancer risk
Authors: Xinfeng Wang, Tomi Jun, Nan Sun, Jie He, Kuan-lin Huang
Journal: Cancer Research (2022)

Abstract Pathogenic germline variants of BRCA1 and BRCA2 disproportionally elevated the risk of specific cancer types (ex. breast [BRCA] and ovarian [OV] cancer) compared to tumors arising from other tissues. The reason underlying the strong tissue-specificity for BRCA-associated cancer risk remains largely unknown. Under the two-hit hypothesis, BRCA-mediated oncogenesis is thought to originate from a cell where the germline BRCA1/2 variant underwent loss of heterozygosity (LOH) of the wildtype BRCA allele, resulting in homologous recombination DNA repair deficiencies. Notably, tumor aneuploidy and loss of chromosome arms also show strong tissue specificity across cancer types. The apparent tissue specificities of BRCA-associated cancer risk and chromosome aneuploidy, together with deletion-induced LOH underlying the two-hit hypothesis, pose an intriguing possibility that they may be linked. Using genomic data from the TCGA PanCanAtlas and ICGC PCAWG projects, we calculated the frequencies of deletions of the chromosomal arms where the BRCA1/2 genes are located (17q for BRCA1; 13q for BRCA2) across different cancer types in tumors with no whole-genome doublings (WGD). Among TCGA cases, OV and BRCA showed significantly higher frequencies of 17q deletion (32.75% and 8.05%, respectively) than other cancer types (ranked 2/30 and 5/30, permutation p-value = 0.030 and 0.024), and relatively higher frequencies of 13q deletion (32.75% and 21.92%, respectively) compared to other cancers (ranked 5/32 and 8/32, p-value = 0.101 and 0.078). As expected, cancer types showing high fractions of BRCA1/2 deletions overlap with those showing 17q/13q deletions and often include BRCA and OV. Subsequently, we determined how often BRCA1/2 deletion co-occurred and thus may be caused by the corresponding 17q/13q deletions, showing that BRCA1 deletion carriers who also had chr17q deletion accounted for 40.76% in OV and 25.93% in BRCA patients, compared to 33.33% in all other cancer types while BRCA2 deletion carriers who also had chr13q deletion accounted for OV (53.97%) and BRCA (58.60%) patients, compared to 49.83% in all other cancer types. In addition, we validated our findings in non-overlapping cases of the ICGC PCAWG projects. Consistent with TCGA results, OV and BRCA showed higher frequencies of 17q and 13q deletion compared to other cancer types. To conclude, we identified a correlation between cross-cancer difference in arm-level and focal chromosome aneuploidy affecting BRCA1/2 and BRCA-associated cancer risk, and how chromosome aneuploid may give rise to tissue-specific risks of cancer remain to be investigated. Citation Format: Xinfeng Wang, Tomi Jun, Nan Sun, Jie He, Kuan-lin Huang. Tissue specificity of chromosome aneuploidy correlates with BRCA-associated cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5692.
Abstract 2169: New telomeres and chromosomal arm fusions in cancer genomes revealed by long-read genome sequencing
Authors: Kar-Tong Tan, Michael K. Slevin, Max Garrity-Janger, Heng Li, Matthew Meyerson
Journal: Cancer Research (2022)

Abstract Chromosomal rearrangements are widespread features of cancer genomes, and often lead to the generation of both larger and smaller chromosomes that are readily observed by cytogenetics analysis. The generation of these chromosomal alterations likely involves alterations in the structure and location of telomeres at chromosome ends, though these events have been difficult to assess due to the long and highly repetitive nature of telomeres. Here, we developed an analytic method (TeloFuse) to identify new telomeres and chromosomal arm fusions which are characterized by telomeric repeats at intra-chromosomal locations. We applied TeloFuse to identify telomere-containing fusions as well as novel sites of telomere addition using short-read genome sequencing data from 326 cancer cell lines followed by long-read genome sequencing and cytogenetic analysis of selected cell lines. We observed new telomeres at sites of terminal deletion in long read data (telomere length = 2-9 kb), and in 76/326 (23%) of cell line genomes with short read data. Telomere sequence-containing fusions at intra-chromosomal sites were detected in 75/326 (23%) of cancer cell lines and confirmed as chromosomal arm fusion events by long-read genome sequencing. Long-read genome sequencing further suggests that new telomeres have similar telomere length as telomeres found on normal chromosomal arms (median = 5kb). Conversely, telomeric repeats at sites of chromosomal arm fusions were found to be critically short (~200-500bp long). Extending our analysis to 97 lung adenocarcinoma patient samples from The Cancer Genome Atlas, we further found new telomeres in 17/97 (18%) and chromosomal arm fusions in 28/97 (29%) patients with short-read data. Notably, new telomeres and chromosomal arm fusion events were also found to disrupt protein-coding genes, suggesting that these events represent a poorly appreciated mode for gene inactivation in cancer. Our results suggest that the formation of new telomeres and chromosomal arm fusions are prevalent events during cancer genome evolution and are likely critical for the stabilization of new chromosomes in human cancers. More broadly, our findings also highlight the utility of long-read genome sequencing in delineating chromosomal-scale alterations that have been widely observed by cytogenetics analysis. Citation Format: Kar-Tong Tan, Michael K. Slevin, Max Garrity-Janger, Heng Li, Matthew Meyerson. New telomeres and chromosomal arm fusions in cancer genomes revealed by long-read genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2169.